Montelukast-intel

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT MONTÉLUCAST-INTELI

Composition:

active substance: montelukast;

1 sachet contains 4.16 mg of montelukast sodium equivalent to 4 mg of montelukast;

excipients: mannitol (E 421), hypromellose, magnesium stearate.

Pharmaceutical form. Granules.

Main physicochemical properties: sachets containing white or almost white granules.

Pharmacotherapeutic group. Drugs for systemic use in obstructive respiratory diseases. Leukotriene receptor antagonists.

ATC code R03DC03.

Pharmacological Properties

Pharmacodynamics

Cysteinyl leukotrienes (LTC4, LTD4, LTE4) are potent inflammatory eicosanoids released by various cells, including mast cells and eosinophils. These key pro-asthmatic mediators bind to cysteinyl leukotriene receptors (CysLT). The CysLT type 1 receptor (CysLT1) is located in human airways (including airway smooth muscle cells and airway macrophages), as well as on other pro-inflammatory cells (including eosinophils and certain myeloid progenitor cells). The presence of CysLT receptors correlates with the pathophysiology of asthma and allergic rhinitis. In asthma, leukotriene-mediated effects include bronchoconstriction, mucus secretion, vascular permeability, and eosinophilia. In allergic rhinitis, CysLT protein is released from the nasal mucosa following allergen exposure during both early- and late-phase reactions, and this is associated with symptoms of allergic rhinitis. Studies have shown that intranasal administration of CysLT increases nasal airway resistance and symptoms of nasal obstruction.

Montelukast, following oral administration, is an active compound that binds with high selectivity and affinity to CysLT1 receptors. Clinical studies have demonstrated that montelukast at a dose of 5 mg inhibits bronchoconstriction induced by inhaled LTD4. Bronchodilation is observed within 2 hours after oral administration, and this effect is additive to bronchodilation induced by β-agonists. Montelukast treatment suppresses both early and late phases of bronchoconstriction caused by antigen stimulation. Compared to placebo, montelukast reduces the number of eosinophils in peripheral blood in adult and pediatric patients. In a separate study, montelukast significantly reduced the number of eosinophils in the airways (measured in sputum) and in peripheral blood, and improved clinical asthma control.

In studies involving adults, montelukast at a dose of 10 mg once daily, compared to placebo, demonstrated significant improvement in morning FEV1 (change from baseline: 10.4% vs. 2.7%, respectively), morning peak expiratory flow (PEF) (change from baseline: 24.5 L/min vs. 3.3 L/min, respectively), and a significant reduction in total use of β-agonists (change from baseline: –26.1% vs. –4.6%, respectively). Improvement in patient-reported daytime and nighttime asthma symptoms was significantly better than with placebo.

Studies in adults demonstrated the ability of montelukast to complement the clinical effect of inhaled corticosteroids (change (% from baseline) for inhaled beclomethasone plus montelukast vs. beclomethasone alone for FEV1: 5.43% vs. 1.04%; β-agonist use: –8.70% vs. 2.64%). Compared to inhaled beclomethasone (200 mcg twice daily, via spacer), montelukast showed a faster initial response, although over the 12-week study period, beclomethasone produced a greater mean therapeutic effect (% change from baseline for montelukast vs. beclomethasone for FEV1: 7.49% vs. 13.3%; β-agonist use: –28.28% vs. –43.89%). However, a higher proportion of patients receiving montelukast achieved a similar clinical response compared to beclomethasone (i.e., approximately 50% of patients receiving beclomethasone achieved an improvement in FEV1 of about 11% or more from baseline, while 42% of patients receiving montelukast achieved the same response).

A clinical study was conducted to evaluate montelukast as a symptomatic treatment for seasonal allergic rhinitis in patients aged 15 years and older with asthma and concomitant seasonal allergic rhinitis. In this study, montelukast tablets administered at a dose of 10 mg once daily demonstrated a statistically significant improvement in the average daily rhinitis symptom score compared to placebo. The average daily rhinitis symptom score is the mean value obtained from assessing nasal symptoms during the day (nasal congestion, rhinorrhea, sneezing, nasal itching) and at night (nasal congestion upon awakening, difficulty falling asleep, frequency of nocturnal awakenings). Significantly better results were obtained for overall patient and physician assessment of allergic rhinitis treatment compared to placebo. Evaluation of the efficacy of this treatment for asthma was not the primary objective of this study.

In an 8-week study involving children aged 6 to 14 years, montelukast at a dose of 5 mg once daily significantly improved respiratory function compared to placebo (change from baseline in FEV1: 8.71% vs. 4.16%; change in morning PEF: 27.9 L/min vs. 17.8 L/min) and reduced the frequency of as-needed β-agonist use (change from baseline: –11.7% vs. +8.2%).

A significant reduction in exercise-induced bronchoconstriction (EIB) was demonstrated during a 12-week study in adults (maximum decrease in FEV1: 22.33% for montelukast vs. 32.40% for placebo; time to recovery within 5% of baseline FEV1: 44.22 min vs. 60.64 min). This effect was maintained throughout the 12-week study period. Reduction in EIB was also demonstrated in a short-term study in children aged 6 to 14 years (maximum decrease in FEV1: 18.27% vs. 26.11%; time to recovery within 5% of baseline FEV1: 17.76 min vs. 27.98 min). The effect in both studies was demonstrated at the end of the dosing interval with once-daily administration.

In patients with aspirin sensitivity receiving ongoing therapy with inhaled and/or oral corticosteroids, montelukast treatment, compared to placebo, resulted in significant improvement in asthma control (change from baseline in FEV1: 8.55% vs. –1.74%; change from baseline in total β-agonist use: –27.78% vs. +2.09%).

Pharmacokinetics

Absorption

Montelukast is rapidly absorbed after oral administration. Following administration of 10 mg film-coated tablets to adults under fasting conditions, the mean peak plasma concentration (Cmax) was achieved at 3 hours (Tmax). The mean bioavailability after oral administration is 64%. A normal meal does not affect the bioavailability or Cmax following oral administration. Safety and efficacy were confirmed in clinical studies with administration of 10 mg film-coated tablets, regardless of meal timing.

For 5 mg chewable tablets, the Cmax in adults was reached within 2 hours after administration under fasting conditions. The mean bioavailability after oral administration is 73% and decreases to 63% when taken with a standard meal.

After administration of 4 mg chewable tablets to children aged 2 to 5 years under fasting conditions, Cmax was reached within 2 hours. The mean Cmax in children was 66% higher than in adults receiving 10 mg tablets, but the mean Cmin was lower.

The 4 mg granules demonstrated bioequivalence to 4 mg chewable tablets in adults under fasting conditions. In children aged 6 months to 2 years, Cmax was reached within 2 hours after administration of 4 mg granules. The Cmax in children was nearly twice that in adults after administration of 10 mg tablets. Administration of granules with apple puree or a high-fat standard meal did not clinically significantly affect the pharmacokinetics of montelukast as determined by AUC (1225.7 and 1223.1 ng·hr/mL after administration with or without puree, respectively, and 1191.8 and 1148.5 ng·hr/mL after administration with or without high-fat standard meal, respectively).

Distribution

Over 99% of montelukast is bound to plasma proteins. The volume of distribution at steady state averages between 8 and 11 liters. In rat studies using radiolabeled montelukast, passage across the blood-brain barrier was minimal. Additionally, concentrations of radiolabeled material in all other tissues 24 hours after dose administration were also minimal.

Metabolism

Montelukast is extensively metabolized. In studies using therapeutic doses, concentrations of montelukast metabolites in plasma at steady state in adults and pediatric patients were not detectable.

Cytochrome P450 2C8 is the primary enzyme involved in the metabolism of montelukast. Additionally, cytochromes CYP 3A4 and 2C9 play a minor role in montelukast metabolism, although itraconazole (a CYP 3A4 inhibitor) did not alter the pharmacokinetic parameters of montelukast in healthy volunteers receiving 10 mg montelukast daily. In vitro studies using human liver microsomes showed that therapeutic plasma concentrations of montelukast do not inhibit cytochromes P450 3A4, 2C9, 1A2, 2A6, 2C19, and 2D6. The contribution of metabolites to the therapeutic effect of montelukast is minimal.

Excretion

The plasma clearance of montelukast in healthy adult volunteers averages 45 mL/min. After oral administration of isotopically labeled montelukast, 86% is excreted in feces within 5 days and less than 0.2% in urine. Combined with the oral bioavailability of montelukast, this indicates that montelukast and its metabolites are almost entirely excreted via bile.

Pharmacokinetics in Specific Patient Populations

Dose adjustment is not required in patients with mild to moderate hepatic impairment. Studies in patients with renal impairment have not been conducted. Since montelukast and its metabolites are excreted via bile, dose adjustment in patients with renal impairment is not considered necessary. There are no data on the pharmacokinetics of montelukast in patients with severe hepatic impairment (Child-Pugh score >9).

Administration of high doses of montelukast (20 and 60 times the recommended adult dose) was associated with decreased plasma theophylline concentrations. This effect is not observed with the recommended dose of 10 mg once daily.

Clinical characteristics.

Indications.

Additional treatment of bronchial asthma in children aged 6 months to 5 years with mild to moderate persistent bronchial asthma that is inadequately controlled by inhaled corticosteroids, as well as in cases of insufficient clinical asthma control with short-acting β-adrenoceptor agonists used as needed.

As an alternative treatment instead of low-dose inhaled corticosteroids for patients aged 2 to 5 years with mild persistent asthma who have not experienced severe asthma attacks requiring oral corticosteroids in the recent past, and who are unable to use inhaled corticosteroids (see section "Dosage and administration").

Prevention of asthma, the predominant component of which is bronchospasm induced by physical exertion, in patients aged 2 years and older.

Contraindications.

Hypersensitivity to the active substance or to any of the excipients.

Interaction with other medicinal products and other forms of interaction.

MONTELUCAST-INTELI may be prescribed together with other medications commonly used for asthma prevention or long-term asthma management. In drug interaction studies, the recommended clinical dose of montelukast had no clinically significant effect on the pharmacokinetics of the following agents: theophylline, prednisone, prednisolone, oral contraceptives (ethinylestradiol/norethindrone 35/1), terfenadine, digoxin, and warfarin.

In patients taking phenobarbital concomitantly, the area under the concentration-time curve (AUC) for montelukast decreased by approximately 40%. Since montelukast is metabolized by CYP 3A4, 2C8, and 2C9, caution is advised, especially in children, when montelukast is co-administered with inducers of CYP 3A4, 2C8, and 2C9, such as phenytoin, phenobarbital, and rifampicin.

In vitro studies have shown that montelukast is a potent inhibitor of CYP 2C8. However, clinical drug interaction studies involving montelukast and rosiglitazone (a marker substrate; a drug metabolized by CYP 2C8) have demonstrated that montelukast is not an inhibitor of CYP 2C8 in vivo. Thus, montelukast does not significantly affect the metabolism of drugs metabolized by this enzyme (e.g., paclitaxel, rosiglitazone, and repaglinide).

In vitro studies have established that montelukast is a substrate of CYP 2C8 and, to a lesser extent, of CYP 2C9 and 3A4. In a clinical drug interaction study using montelukast and gemfibrozil (an inhibitor of CYP 2C8 and 2C9), gemfibrozil increased systemic exposure to montelukast by 4.4-fold. When montelukast is used concomitantly with gemfibrozil or other potent inhibitors of CYP 2C8, dose adjustment of montelukast is not required, but physicians should consider the increased risk of adverse reactions.

Based on in vitro studies, clinically significant interactions are not expected with weaker inhibitors of CYP 2C8 (e.g., trimethoprim). Concomitant administration of montelukast with itraconazole, a strong inhibitor of CYP 3A4, did not result in a significant increase in systemic exposure to montelukast.

Special precautions for use

The diagnosis of persistent bronchial asthma in children aged 6 months to 2 years should be established by a pediatrician or pulmonologist.

Patients should be advised that MONTLUCAST-INTELI for oral use should never be used to treat acute asthma attacks, and that they should always have access to appropriate rescue medication. Short-acting inhaled β-agonists should be used during acute attacks. Patients should seek medical advice as soon as possible if they require more frequent use of short-acting β-agonists than usual.

Inhaled or oral corticosteroid therapy should not be abruptly replaced with montelukast.

There are no data confirming that the dose of oral corticosteroids can be reduced when montelukast is used concomitantly.

Neuropsychiatric events have been reported in patients taking montelukast (see section "Side effects"). Since other factors may influence these events, it is unknown whether they are related to the use of MONTLUCAST-INTELI. Physicians should discuss these adverse events with their patients and/or caregivers. Patients and/or caregivers should be instructed to inform their physician if such changes occur. Physicians should carefully evaluate the risks and benefits of continuing the medication if such reactions occur.

In rare cases, systemic eosinophilia, sometimes accompanied by clinical signs of vasculitis, such as Churg-Strauss syndrome, has been observed in patients receiving anti-asthma medications, including montelukast. This condition is treated with systemic corticosteroid therapy. These cases were usually (but not always) associated with a reduction in dose or discontinuation of corticosteroid therapy. The possibility that leukotriene receptor antagonists may be linked to the development of Churg-Strauss syndrome cannot be definitively ruled out or confirmed. Physicians should be aware of the potential for eosinophilia, vasculitic rash, worsening pulmonary symptoms, cardiac complications, and/or neuropathy in patients. Patients who develop such symptoms should be re-evaluated and their treatment regimen reviewed.

Treatment with montelukast does not allow patients with aspirin-induced asthma to use aspirin or other nonsteroidal anti-inflammatory drugs.

The medicinal product contains less than 1 mmol (23 mg) of sodium per sachet, i.e., it is practically sodium-free.

Use during pregnancy or breastfeeding

This medicinal product can be used in children aged 6 months to 5 years.

Ability to influence reaction rate when driving or operating machinery

This medicinal product is intended for use in children aged 6 months to 5 years.

Dosage and Administration

MONTELUKAST-INTELI 4 mg granules should be administered under adult supervision. The dose for children aged 6 months to 5 years is one 4 mg sachet once daily, taken in the evening. Dose adjustment is not required in this age group. Clinical data on efficacy in children aged 6 months to 2 years with persistent asthma are limited. The patient's therapeutic response to montelukast treatment should be evaluated within 2 to 4 weeks. If no response is observed, treatment should be discontinued. MONTELUKAST-INTELI 4 mg granules are not recommended for children under 6 months of age.

Administration of Montelukast Granules

Montelukast granules may be taken directly by mouth or mixed with a spoonful of soft food at room temperature or cold (e.g., applesauce, ice cream, carrots, or rice). The sachet should not be opened in advance. After opening, the entire contents of the sachet should be taken immediately (within 15 minutes). If taken with food, the prepared granules must not be saved for later use. The granules should not be dissolved in liquid prior to administration; however, they may be followed by a drink of liquid. Montelukast granules may be taken regardless of meals.

General Recommendations

The therapeutic effect of montelukast on asthma control parameters begins within one day. Patients should be advised to continue taking montelukast even when asthma symptoms are controlled and during asthma exacerbations.

Dose adjustment is not required in patients with renal impairment or mild to moderate hepatic impairment. Data in patients with severe hepatic impairment are lacking. Dosage is the same for boys and girls.

Use of Montelukast as an Alternative to Low-Dose Inhaled Corticosteroids in the Treatment of Mild Persistent Asthma

Montelukast is not recommended as monotherapy for patients with moderate persistent asthma. Use of montelukast as an alternative to low-dose inhaled corticosteroids in patients aged 2 to 5 years with mild persistent asthma should be considered only if these patients have not recently experienced severe asthma attacks requiring oral corticosteroids and have demonstrated inability to use inhaled corticosteroids. Mild persistent asthma is defined as asthma with symptoms occurring more than once per week but less than once per day, nocturnal symptoms more than twice per month but less than once per week, and normal lung function between episodes. If adequate control of such asthma cannot be achieved within approximately one month, consideration should be given to initiating other or additional anti-inflammatory therapies according to a stepwise asthma treatment approach. Patients should be periodically evaluated for asthma control and overall asthma status.

Use of Montelukast for Prevention of Exercise-Induced Bronchospasm in Patients Aged 2 to 5 Years

Exercise-induced bronchospasm in patients aged 2 to 5 years may be the primary manifestation of persistent asthma requiring treatment with inhaled corticosteroids. The condition of such patients should be evaluated within 2 to 4 weeks of starting montelukast therapy. If an adequate therapeutic response is not achieved, additional or alternative treatment should be considered.

Combination of Montelukast Therapy with Other Asthma Treatments

When montelukast is used as add-on therapy to inhaled corticosteroids, inhaled corticosteroids should not be abruptly replaced by montelukast.

Adults and adolescents aged 15 years and older may take 10 mg film-coated tablets.

For children aged 6 to 14 years, 5 mg chewable tablets are available.

For children aged 2 to 5 years, 4 mg chewable tablets are available.

Children. MONTELUKAST-INTELI 4 mg granules are not recommended for children under 6 months of age.

Overdose

Detailed information on the management of montelukast overdose is limited. In clinical studies of chronic asthma, patients received montelukast at doses up to 200 mg/day for 22 weeks and up to 900 mg/day for approximately one week in short-term studies, with no clinically significant adverse reactions reported.

In post-marketing experience and clinical trials of montelukast, cases of acute overdose have been reported. These include reports of adults and children who ingested doses up to 1000 mg (approximately 61 mg/kg in a 42-week-old child). Clinical and laboratory findings were consistent with the safety profile observed in adults and children. In most cases, no adverse reactions were reported. The most commonly reported adverse reactions were consistent with the known safety profile of montelukast and included abdominal pain, somnolence, thirst, headache, vomiting, and psychomotor hyperactivity.

Treatment

It is unknown whether montelukast is removed by peritoneal dialysis or hemodialysis.

Adverse reactions

Montelukast was evaluated in clinical studies:

film-coated tablets 10 mg – in approximately 4,000 asthma patients aged 15 years and older;

film-coated tablets 10 mg – in approximately 400 patients with asthma and seasonal allergic rhinitis aged 15 years and older;

chewable tablets 5 mg – in approximately 1,750 asthma patients aged 6 to 14 years;

chewable tablets 4 mg were studied in 851 children aged 2 to 5 years;

granules 4 mg were studied in 175 children aged 6 months to 2 years.

During clinical studies, the following adverse reactions were reported frequently (≥1/100 to <1/10) in patients receiving montelukast treatment and more frequently than in patients receiving placebo.

Table 1

During clinical studies with prolonged treatment of a small number of adult patients for 2 years and children aged 6 to 14 years for 12 months, the safety profile did not change.

Overall, 502 children aged 2 to 5 years received montelukast treatment for at least 3 months, of whom 338 children were treated for 6 months or longer, and 534 children for 12 months or longer. During long-term treatment, the safety profile in these patients did not change.

The safety profile in children aged 6 months to 2 years did not change during treatment lasting up to 3 months.

Post-marketing period

Adverse reactions reported during the post-marketing period are listed according to system organ classes and specified terms in Table 2. Frequencies are based on data from relevant clinical studies.

Table 2

Reporting of suspected adverse reactions

Reporting adverse reactions following the authorization of a medicinal product is of great importance. It enables ongoing monitoring of the benefit-risk balance of the medicinal product. Healthcare and pharmaceutical professionals, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of efficacy of the medicinal product via the Automated Information System for Pharmacovigilance at the following link: https://aisf.dec.gov.ua

Shelf life. 2 years.

Storage conditions.

Store at temperatures not above 30 °C in the original packaging. Keep out of reach and sight of children.

Packaging.

Granules in sachets. 28 sachets in a cardboard box.

Prescription status.

Prescription only.

Manufacturer.

LABORATORIOS NORMON, S.A.

Manufacturer's address and address of the site of manufacture.

Ronda de Valdecarrizo, 6, Tres Cantos 28760 (Madrid), Spain.